Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-01-11
1999-02-02
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 19, 530330, 530331, 562571, A61K 3800, C07K 500
Patent
active
058665455
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to substituted ketone derivatives of Formula I useful in the treatment of inflammation in lung, central nervous system, kidney, joints, endocardium, pericardium, eyes, ears, skin, gastro-intestinal tract and urogenital system. More particularly, this invention relates to substituted ketone derivatives that are useful inhibitors of interleukin-1.beta. converting enzyme (ICE). Interleukin-1.beta. converting enzyme (ICE) has been identified as the enzyme responsible for converting precursor interleukin-1.beta. (IL-1.beta.) to biologically active IL-1.beta.. ##STR2##
Mammalian interleukin-1 (IL-1) is an immunoregulatory protein secreted by cell types as part of the inflammatory response. The primary cell type responsible for IL-1 production is the peripheral blood mono-cyte. Other cell types have also been described as releasing or containing IL-I or IL-I like molecules. These include epithelial cells (Luger, et al., J. Immunol. 127: 1493-1498 (1981), Le et al., J. Immunol. 138: 2520-2526 (1987) and Lovett and Larsen, J. Clin. Invest. 82: 115-122 (1988), connective tissue cells (Ollivierre et al., Biochem. Biophys. Res. Comm. 141: 904-911 (1986), Le et al, J. Immunol. 138: 2520-2526 (1987), cells of neuronal origin (Giulian et al., J. Esp. Med. 164: 594-604 (1986) and leukocytes (Pistoia et al., J. Immunol. 136: 1688-1692 (1986), Acres et al., Mol. Immuno. 24: 479-485 (1987), Acres et al., J. Immunol. 138: 2132-2136 (1987) and Lindenmann et al., J. Immunol 140: 837-839 (1988).
Biologically active IL-I exists in two distinct forms, IL-1.alpha. with an isoelectric point of about pI 5.2 and IL-162 with an isoelectric point of about 7.0 with both forms having a molecular mass of about 17.5 kDa (Bayne et al., J. Exp. Med. 163: 1267-1280 (1986) and Schmidt, J. Exp. Med. 160: 772 (1984). The polypeptides appear evolutionarily conserved, showing about 27-33% homology at the amino acid level (Clark et al., Nucleic Acids Res. 14: 7897-7914 (1986).
Mammalian IL-1.beta. is synthesized as a cell associated precursor polypeptide with a molecular mass of about 31 kDa (Limjuco et al., Proc. Natl. Acad. Sci USA 83: 3972-3976 (1986). Precursor IL-1.beta. is unable to bind to IL-1 receptors and is biologically inactive (Mosley et al., J. Biol. Chem. 262: 2941-2944 (1987). Biological activity appears dependent upon some form of proteolytic processing which results in the conversion of the precursor 31 kDa form to the mature 17.5 kDa form. Evidence is growing that by inhibiting the conversion of precursor IL-1.beta. to mature IL-1.beta., one can effectively inhibit the activity of interleukin-1.
Mammalian cells capable of producing IL-1.beta. include, but are not limited to, keratinocytes, endothelial cells, mesangial cells, thymic epithelial cells, dermal fibroblasts, chondrocytes, astrocytes, glioma cells, mono-nuclear phagocytes, granulocytes, T and B lymphocytes and natural killer cells.
As discussed by J. J. Oppenheim, et al., Immunology Today, vol. 7(2):45-56 (1986), the activities of interleukin-1 are many. It has been observed that catabolin, a factor that promotes degradation of cartilage matrix, also exhibited the thymocyte co-mitogenic activities of IL-1 and stimulates chondrocytes to release matrix metalloproteinases and plasminogen activator. In addition, a plasma factor termed `proteolysis inducing factor` stimulates muscle cells to produce prostaglandins which in turn leads to proteolysis, the release of amino acids and, in the long run, muscle wasting, and appears to represent a fragment of IL-1 with fever-inducing, acute phase response and thymocyte co-mitogenic activities.
IL-1 has multiple effects on cells involved in inflammation and wound healing. Subcutaneous injection of IL-1 leads to margination of neutrophils and maximal extravascular infiltration of the polymorphonuclear leukocytes (PMN). In vitro studies reveal IL-1 to be a chemotactic attractant for PMN, to activate PMN to metabolize glucose more rapidly, to reduce nitroblue tetrazolium, and to release
REFERENCES:
patent: 4481192 (1984-11-01), Cazaubon et al.
patent: 4582821 (1986-04-01), Kettner et al.
patent: 5055451 (1991-10-01), Krantz et al.
patent: 5169935 (1992-12-01), Hoeger et al.
patent: 5283293 (1994-02-01), Webb
patent: 5324833 (1994-06-01), Sieber et al.
Banerjee, et al Chem. Abstracts vol. 92 (17), p. 633 Ab #147159s (1980).
Black, et al, J. Biol. Chem. vol. 263, pp. 9437-9442 (1988).
Black, et al, J. Biol. Chem. vol. 264, pp. 5323-5326, (1988).
Black, et al, Feb. Lett. vol. 247, pp. 286-290 (1989).
Howard, et al, J. Immunology vol. 147, pp. 2964-2969 (1991).
Kostura, et al, Proc. Natl. Acad. Sci. vol. 86, pp. 5227-5231 (1989).
Moon, et al, J. Am. Chem. Soc. vol. 198, pp. 1350-1351 (1986).
Pat Abstr. of Japan, vol. 13 (227) (C-600) (3575) (May 25, 1989).
Ressler, et al, J. Org. Chem. vol. 36 (25), pp. 3960-3966 (1971).
Sleath, et al, J. Biol. Chem. vol. 265, pp. 14526-14528 (1990).
Thornberry, et al, Nature, vol. 356, pp. 768-774 (Apr. 30, 1992).
Weidner, et al, Peptides, Chemistry, Biology, Proceeding of the 12th American Peptide Symposium, Jun. 16-21, 1991 Cambridge, Mass., USA pp. 891-892 (1992).
Gross, The Peptides, vol. 3, pp. 101-104 (1981).
Hagmann William K.
Maccoss Malcolm
Mjalli Adnan M.
Zhao Justin J.
Celsa Bennett
Merck & Co. , Inc.
Panzer Curtis C.
Rose David L.
Tsang Cecilia J.
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